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Designer biopolymer speaks nucleic acid and protein languages

Peptide nucleic acids with amino acid side chains can target disease-related RNA

by Laura Howes
November 21, 2019 | A version of this story appeared in Volume 97, Issue 46


The basic structure of the PNA monomers with hydrophobic or hydrophilic amino acids at the γ position.
Adding hydrophobic or hydrophilic amino acid side chains at the γ position (R) of a PNA's individual backbone peptide units enables PNA strands to self-assemble into spherical aggregates.

If you’ve ever learned a language, says Jen Heemstra of Emory University, there are two levels of understanding. First you learn to read text and comprehend it. Then you begin speaking the language and interacting with others. In Heemstra’s lab, she says her team members are even more ambitious: the group is teaching molecules to speak both nucleic acid and protein languages simultaneously (J. Am. Chem. Soc. 2019, DOI: 10.1021/jacs.9b09146). (Heemstra partners with C&EN to write a monthly column, Office Hours.)

Peptide nucleic acids (PNAs) are artificial polymers that were originally invented in 1991 to be synthetic mimics of DNA. Instead of having a deoxyribose phosphate backbone like DNA, PNA has a pseudopeptide polymer backbone to which nucleobases are linked. The resulting biopolymer is stabler than DNA, yet it can still “speak,” or interact, with complementary RNA or DNA strands.

The new innovation in PNA coming from Heemstra’s PhD student Colin Swenson is to enable PNA to speak protein as well. Swenson added hydrophilic and hydrophobic amino acid side chains to different PNA monomers so that the PNA could be assembled with a pattern of hydrophobicity and a nucleobase code. These different amino acid side chains drive the PNA strands to self-assemble into spheres with their hydrophobic segments in the center and their hydrophilic bits on the outside. Binding with complementary DNA or RNA codes can then cause the spheres to disassemble again.

The idea is that these tiny aggregates can enter cells and target an RNA sequence that’s upregulated in cancer. The team showed that when the aggregates come upon the correct RNA in solution, they disassemble, and their individual PNA strands bind to the RNA strands. In cancer cells, this would ideally stop the RNAs from participating in gene expression.

This isn’t the first time scientists have added hydrophobic portions to PNA strands, but in the past they’ve typically done so by grafting separate polymers to PNA to create conjugates in which each segment or length of the resulting polymer has a different property. In this new work, these different properties have been incorporated into the peptide backbone of PNA itself.

“I think these bilingual PNAs have tremendous potential for therapeutic delivery, as the actual PNA is the cargo and container all in one—rather than conventional therapeutic delivery agents always being separate from the cargo,” says Jin Kim Montclare of New York University, who designs novel proteins for drug delivery and medical treatments. It is, she adds, very clever packaging.

Heemstra sees more applications for the bilingual PNAs in the future. Perhaps, she suggests, her group can encode more structural complexity into the protein backbone or add amino acid segments to the PNAs that can interact with protein surfaces too. “When our imaginations run wild we start to ask, Can we have adapters and switches?” she says. “Thinking about all the ways that, you know, human translators work. Can we do those sorts of things with biomolecules?”

Heemstra and her team are now talking to potential computational collaborators to help with those designs, she says. She hopes the work might grow into a new subfield of PNA materials. “That’s why,” she says, “we’re just incredibly, incredibly excited about it.”

The graphic accompanying this article was updated on Nov. 22, 2019, to clarify how the PNA aggregates assemble.


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